Thrormbocytopenia is one of the most common hematologic problems among patients in Neonatal Intensive Case Units (NICU), affecting 20-35 percent of NICU patients. In 20-25 percent of these patients the thrombocytopenia is severe and requires treatment with platelet transfusions. In adults, the administration of recombinant thrombopoietin (rTpo) is being investigated as an alternative to platelet transfusions. Our previous in vitro and in vivo studies have shown that megakaryocyte progenitors of neonates are more sensitive to rTpo than are megakaryocyte progenitors of adults, suggesting that rTpo administration could be an effective therapy for thrombocytopenic neonates. Since rTpo does not increase the platelet count until 4 to 6 days after starting therapy, the only appropriate candidates would be neonates whose thrombocytopenia is severe and prolonged. However, the application of new therapies to thrombocytopenic neonates has been significantly hampered by our lack of understanding of even the basic kinetic mechanisms responsible for their thrombocytopenias (platelet destruction versus decreased platelet production). With the development of rTpo, there is now a pressing need to clarify these mechanisms in neonates with severe and prolonged thrombocytopenia. With this in mind, we propose to; (1) identify the kinetic mechanisms responsible for severe and prolonged thrombocytopenia in NICU patients, (2) establish the correlation between peripheral blood and bone marrow indicators of thrombopoiesis in thrombocytopenic neonates, and (3) conduct a multicenter, open-label, phase I/Il, dose-escalation trial of rTpo administration to neonates with severe and prolonged thrombocytopenia. The first two studies will use techniques specifically developed for the study of megakaryocyte number, size, and ploidy in the bone marrow of neonates, and will correlate these with newly developed indirect measures of thrombopoiesis (i.e. reticulated platelet counts, serum Tpo concentrations, and circulating megakaryocyte progenitors). The last study will test the biological effects, pharmacokinetics, and safety of rTpo administration to neonates with prolonged and severe thrombocytopenia.